Prostate cancer (PCa) is one of the most common cancers, with a mortality rate that is among the top five worldwide. Moreover, it is the second most frequently diagnosed cancer among men (1). Most PCa patients are diagnosed when the disease is only localized, which means that many patients could be curable if the disease is detected in the early stages. In contrast, approximately 30% of patients will have cancer recurrence. Therefore, it is important to find more accurate prognoses and predictive markers for the treatment of PCa.

Before that, many indicators have been shown to be closely related to the prognosis of prostate cancer. For example, Gleason score, metastases, pain phosphatase, alkaline, and albumin were prognostic factors for several survival indicators of PCa (2–5). Moreover, systemic inflammation was discussed as a predictive factor for the survival of PCa patients in some studies (6). Some studies also showed that anti-inflammatory drugs had a protective effect on PCa patients (7).

C-reactive protein (CRP) is mainly produced by the liver as a typical acute-phase protein, which is one of the most common markers of systemic inflammation and is routinely measured (8). The elevation of CRP level was discussed as a prognostic indicator for many cancers, such as lung cancer, breast cancer, and colorectal cancer (9). It is also associated with the prognosis of urological cancers such as renal cell carcinoma (10, 11).

In the past few years, the relationship between CRP levels and the prognosis of prostate cancer patients remains controversial. Some studies suggested that PCa patients with elevated CRP levels often had worse survival (12, 13). Some other studies had different views and believed that there was no significant correlation between the CRP level and the prognosis of prostate cancer patients (14–16). The results of these studies were different, and due to their small sample size, the results were not very reliable. Therefore, we performed this meta-analysis by summarizing all credible articles to explore the relationship between C-reactive protein levels and prognosis in prostate cancer. Then, subgroup analysis was performed by staging the disease.

This was a meta-analysis of C-reactive protein levels and prognosis in prostate cancer. We found that PCa patients often had worse survival with high levels of CRP. The results further confirmed the study of Liu et al. (21). Moreover, we also performed subgroup analyses by staging the disease because of the bigger sample size. Our study also indicated that the level of CRP was related to the survival of both mPCa patients and localized PCa patients.

As prostate cancer is the most common malignancy in the male reproductive system, its treatment is varied. It could be roughly divided into wait and watch, active monitoring, surgical treatment, radiotherapy, androgen deprivation therapy (ADT), etc. (22). However, mPCa is still deadly, with a 5-year survival rate of approximately 30%, indicating the need for better treatment options. In recent years, there are also some new advances in the treatment of prostate cancer. Arpit et al. found that rucaparib and olaparib (poly-ADP-ribose polymerase (PARP) inhibitors) could be used as the targeted therapy option for patients with mPCa (23). Arnas et al. suggested that high-intensity focused ultrasound (HIFU) has a high control rate and safety in the treatment of local prostate cancer patients and should be promoted in clinical treatment (24). Jiang et al. also found that nanotechnology could create good synergy with radiotherapy, chemotherapy, thermotherapy, photodynamic therapy, and gene therapy, which could increase the effectiveness of treatment and reduce drug resistance (25). With the recent advances, the treatments of prostate cancer became varied, so it was particularly important to evaluate the prognosis of prostate cancer patients.

In recent years, diversified predictors have been confirmed for predicting the prognosis of PCa. One of the most commonly used prostate-specific antigens was the conventional measurement index in the treatment of all PCa patients. In addition, many studies found that epidermal growth factor receptor (EGFR), pAkt, nuclear factor-kappa B, macrophage inhibitory cytokine-1 (MIC-1), matrix metalloproteinase-1 (MMP-1), MMP-9 and tissue inhibitor of metalloproteinase-2 (TIMP-2), and macrophage inhibitory cytokine-1 were associated with the outcome of PCa patients (26, 27). However, in fact, all the above biomarkers must be tested in pathological tissues. This made it difficult for real-time monitoring of the prognosis of patients. Instead, the inflammation indicators were easy to examine from the blood. Brown et al. found that an inflammation-based prognostic score (Glasgow Prognostic Score) was associated with advanced lung and gastrointestinal cancers for the first time (28). After that, the Glasgow Prognostic Score was found to be related to many types of cancer. Recently, one study found that the prognostic value of the Glasgow Prognostic Score in PCa patients, the elevation of CRP (>10 mg/L), and hypoalbuminemia (<35 g/L) were related to worse prognoses of PCa patients (6). William Khalil et al. also summarized the hematological indicators related to the prognosis of prostate cancer, including collagenases, stromelysins, TIMP-1 and TIMP-2, MMP-13, osteopontin (OPN), MMP-2, MMP-9, and MMP-7 (29). Maria et al. also considered the following blood indicators to be associated with the prognosis of prostate cancer: prostate-specific antigen (PSA) + kallikrein antigen (KLK2), AKT, chromogranin A (CHGA), and early prostate cancer antigen (EPCA) (30). Katalin et al. also considered that the following blood-derived biomarkers played an important role in the prognosis of prostate cancer: circulating tumor cells, cellular and soluble immunological and inflammation-related blood markers, and extracellular vesicles and their microRNA content (31). However, the inflammation indicators could be more easily detected from the blood and are widely used in the clinical setting. CRP is the most common indicator of inflammation and has also been widely studied in recent years.

There are many possible mechanisms for the elevation of CRP with worse survival in cancer patients. Chronic inflammation could promote the growth of vascular endothelial cells, which was beneficial to the occurrence of tumors (32). On the one hand, the inflammatory reaction could be activated by the rapid growth of the tumor. Many inflammatory factors are released when the tumor is growing. On the other hand, inflammation also could provide a microenvironment for the growth of tumors, for example, survival factors and growth factors (33). Moreover, a significant negative correlation was recently found between the elevation of CRP and T-lymphocyte subset infiltration (34). Therefore, our study is necessary for the advancement in the treatment of PCa.

The level of CRP is also important for the outcome in PCa. Sevcenco et al. suggested that patients are more prone to experience biochemical recurrence (BCR) with high levels of CRP (35). Hall et al. performed multivariable analysis and found that a higher CRP level is an independent prognostic factor for BCR in patients with radiotherapy (36). According to the multivariate analysis of McArdle et al., a CRP level >10 mg dl⁻¹ before a diagnosis is an independent prognostic factor for both OS and CSS of PCa patients (37). Otherwise, Arthur et al. found that elevated CRP is associated with increased odds of both a high risk and metastatic PCa and high PSA levels, which means that the level of CRP would rise with the increase of tumor stage and disease progression for PCa patients (38). Sevcenco et al. also found that the patients with higher Gleason scores on biopsy, lymph node metastasis, seminal vesicle invasion, extracapsular extension, and positive surgical margins status often had a higher level of CRP compared with patients without these features (35). This further confirmed this conclusion, but more studies are needed to confirm the conclusions.

Firstly, we analyzed the association between the elevation of CRP and the prognosis of PCa patients. We found that CRP level could be a prognosis predictor of PCa in both categorized data and log data. The result showed that elevated CRP levels were associated with worse OS, CSS, and PFS in PCa patients. However, significant heterogeneity was observed; the heterogeneity might be due to many aspects, for example, basic characteristics, the staging of the disease, follow-up time, the difference in treatment, and the different cutoff values. Therefore, we chose a random-effects model to reduce the effect of these differences. Otherwise, we performed a subgroup analysis by the staging of the disease according to the characteristics of these studies and found that the heterogeneity was significantly reduced, which meant that the staging of the disease was likely to be the source of heterogeneity. The result further confirmed that CRP level could be a prognosis predictor for PCa.

For mPCa, we found a significant association between high CRP levels and worse OS in mPCa. For localized PCa, a significant association also could be observed between elevated CRP levels and worse OS, CSS, and PFS. Furthermore, we found that heterogeneity was significantly reduced, which indicated that the staging of the disease contributed to the source of heterogeneity. Our meta-analysis proved that an elevated CRP level is a strong prognosis predictor of PCa patients, which could be helpful for the treatment of PCa. It also could help doctors better monitor the progress of the disease.

Our research includes more new studies compared with the research of Liu et al. (21). Moreover, we also performed Begg’s test to make our results more credible and the subgroup analysis by staging the disease, explored the relationship between CRP and the survival of patients with different stages of PCa, and found the source of heterogeneity.

However, our study also has some limitations. There is also a need for more credible studies to confirm our conclusions, although we have reviewed all the current literature. The heterogeneity was significant in our study, but we performed stratified analysis to reduce the heterogeneity, which made the results more credible. In addition, the techniques for detecting CRP were different, which made the results unreliable.

In general, our meta-analysis found that elevated CRP levels were related to worse OS, CSS, and PFS in PCa patients. Furthermore, we also observed the same relationship between CRP and the survival of localized PCa patients. Therefore, it can be indicated that the CRP level could be used as a prognosis predictor of prostate cancer. More studies are needed to confirm these conclusions.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

i) Conception and design: KZ. ii) Administrative support: BM. iii) Provision of study materials or patients: KZ and XZ. iv) Collection and assembly of data: BM, CL and KZ. v) Data analysis and interpretation: KZ, CL and TC. vi) Manuscript writing: KZ and CL. All authors contributed to the article and approved the submitted version.